The glucocorticoid receptor is part of the family of nuclear receptors. The receptor is a nuclear transcription factor that when bound to a ligand promotes or suppresses the transcription of genes. Glucocorticoid receptor agonists occur naturally or may be prepared synthetically. Examples of synthetic glucocorticoid receptor agonists include prednisolone and dexamethasone. Glucocorticoid receptor agonists possess valuable anti-inflammatory properties and have found widespread use in the art in controlling wide range of allergic and inflammatory conditions, such as asthma, rheumatoid arthritis, eczema, psoriasis and others (see, for example, Barnes, P. “Corticosteroids: The drugs to beat” European Journal of Pharmacology 2006, 533, p. 2-14). Unfortunately, the therapeutic potential of this class of compounds has not been fully maximized because of the existence of adverse side effects, which limit the dose of drug that may be administered to the patient or the time period for which the agonist may be administered to the patient. Side effects include suppression of hypothalamic-pituitary-adrenal axis, bone demineralization and osteoporosis, ocular side effects (e.g., glaucoma, cataracts), growth retardation in children, disruption of carbohydrate metabolism.
Hence, a goal in the art has been the development of glucocorticoid receptor agonists that exhibit reduced side effects. One approach has been the development of glucocorticoids that can be administered by inhalation. Agents administered in this manner exhibit a higher safety profile because they posses low systemic bioavailability; this due to the combination of inhaled administration, slow pulmonary absorption and rapid clearance (see, for example, Flogger, P. “Current Concepts for Optimizing the Therapeutic Index of Glucocorticoid Receptor Ligands for Oral and Inhalative Use: Basic Considerations and Clinical Reality”, Current Medicinal Chemistry -Anti-Inflammatory &Anti-Allergy Agents 2003, 2, p. 395-408). Examples of compounds developed following this approach include fluticasone propionate and its structurally related analogues (see, e.g., U.S. Pat. No. 4,335,121), mometasone furoate and its structurally related analogues (see, e.g., U.S. Pat. No. 4,472,393), or more recently, analogues disclosed in WO 2002/12265.
A problem associated with inhaled glucocorticoids is that while they exhibit improved safety profiles at low therapeutic doses, their safety profile decreases at higher doses or when these agents are administered for a long period of time. Hence, while this approach has advantages over earlier-developed glucocorticoids, there remains a need in the art for glucocorticoids that can be administered at higher doses, for longer periods of time or both, thereby permitting one to expand the scope of disease states that can be treated or allowing one to reduce the undesired side effects.
Another approach is to discover compounds where the metabolic effects, which cause the undesired side effects, are dissociated from the anti-inflammatory effects. The discovery of steroids in which anti-inflamatory activity has been separated from the metabolic activity would be an advance in this art.
Steroid-based and nonsteroidal-based glucocorticoids analogues are well known in this art. For example, WO 1999/041256 describes glucocorticoids selective anti-inflammatory agents of nonsteroidal nature. GB 2,018,256, U.S. Pat. No. 3,989,686, U.S. Pat. No. 4,263,289, and EP 0 004 773 describe 17 thiocarboxylic acid steroid derivatives. WO 1997/23565 describes lactone derivatives of 17-β-carboxy, carboxythio, and amide andronstane derivative with anti-inflammatory or anti-allergic properties. WO 2006/043015 reports that the 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-pro-pionyloxy-androsta-1,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl)ester of the formula:
possesses useful anti-inflammatory activity, while having little or no systemic activity. Other derivatives are disclosed in WO 1997/24368, WO 2000/64882, WO 2003/035668, CN1414008, U.S. Pat. No. 3,598,816 and U.S. Pat. No. 5,645,404.
U.S. Pat. No. 4,861,765, discloses 21-substituted thioether glucocorticoid steroid derivatives of the formula:
that are reported to have reduced systemic side effect and excellent anti-inflammatory properties. U.S. Pat. No. 5,420,120, also discloses 21-substituted thioether glucocorticoid steroid derivatives similar to those disclosed in U.S. Pat. No. 4,861,767; these compounds are said to be effective topical anti-inflammatory agents for the treatment of ophthalmic inflammatory disorders. Other C21-substituted thioether derivatives are disclosed in WO 1997/24367, U.S. Pat. No. 3,687,942 and S. Wu et al., Ann. Chim. Acta, vol 268, pp. 255-260 (1992).
DE20211718 discloses C21-substituted phenyl ether steroid derivatives. And WO95/18621 discloses steroids, including 6alpha,9alpha-fluoro-11beta,17-dihydroxy-16alpha-methyl-pregna-1,4-diene-3-one-17-carboxylic acid and related compounds. According to the description, the steroids disclosed in WO95/18621 have angiostatic activity and reduced glucocorticoid activity. One such compound exemplified (in example 23) in WO95/18621 has the following structure:
